Steroid and intermediate compounds



United States Patent 2,810,758 STEROID AND INTERMEDIATE COWQUNDS WilliamS. Johnson, Madison, Wis., Brian Bannister, Kalamazoo, Mich., and EdgarR. Rogier, Minneapolis, Minn., assignors to Wisconsin Alumni ResearchFoundation, Madison, Wis., a corporation of Wisconsin No Drawing.Application May 26, 1955, Serial No. 511,396

13 Claims. (Cl. 260-586) The present invention relates to the steroidfield. More specifically the invention is directed to improved processesand resulting products having particular utility in the synthesis ofnon-aromatic steroids. The invention also includes a novel,physiologically active, non-aromatic steroid produced by the processesand employing the intermediates of our invention.

In the copending application of William S. Johnson, Serial No. 301,369,filed July 28, 1952, and now abandoned, there is disclosed the productl-methoxy-S-keto- IOa-methyl 5,6,8,9,10,10a,11,12 octahydrochrysene (I,where R is methyl) and processes of preparing the same. The presentinvention is concerned with the selective reduction of the double bondsat the 6a,7- and 4b,10b-positions as well as of the carbonyl group atCa. The tetracyclic ketone I was treated with ethyl orthoformate toproduce the crystalline enol ethyl ether II, M. P. 136, with A max. 227m (log 6 4.58), which is characteristic of the diene structure and showsthat the styrene double bond remained at 4b, 10b and had not migrated tothe alternate 4b,5-position. The structure was confirmed by hydrolyticregeneration of the tetracyclic ketone I. The 6,6a-double bond of theenol ether was selectively hydrogenated over palladium-on-strontiumcarbonate giving a product which did not appear to be homogeneous, andprobably consisted of a mixture of the dihydro enol ether with thedouble bond at 7, 8 and 8, 9. The latter, which is a rearrangementproduct of the former, corresponds to the structure that was establishedfor the dihydro enol ether of cholestenone. Acid hydrolysis of thedihydro enol ether gave a single product, M. P. 176, which has beenshown to be the expected A/B transdihydro ketone IV. The ultravioletabsorption spectrum of IV, A max. 222 and 265.5, is typical of them-methoxy-styrene chromophore. The min. at 244 mu (log 6 3.88) ascompared with the intense absorption (log e about 4.35) for thetetracyclic ketone I clearly shows that the nae-unsaturated ketonechromophore was lost, and that the 6a,7- double bond was indeed reduced.

The enol acetate XVI, M. P. 138, was formed readily from the tetracyclicketone 1. Reduction of XVI with sodium borohydride yielded a dihydroalcohol represented by Formula XVII.

Hydrogenation of the tetracyclic ketone I over palladium-on-carbon inthe presence of a trace of potassium hydroxide resulted instereoselective reduction to give a new dihydro ketone, M. P. 121, inhigh yield. The ultraviolet spectrum was identical with that of IVshowing only the m-methoxystyrene chromophore; hence the newstereoisomer must be the A/B-cis-dihydroketone XI.

Both dihydro ketones 1V and XI underwentstereoselective reduction withlithium'aluminum hydride to give crystalline hydroxy compoundsformulated as VII (hydroxyl 85) and X (hydroxyl 80:), respectively. Itis noteworthy that the reduction product of IV gave a precipitate withdigitonin while that from XI did not, which is consistent with the andan orientation of the hydroxyl groups, respectively.

ice

Catalytic hydrogenation of the A/B trans-dihydro ketone IV over 30%palladium hydroxide-on-strontium carbonate proceeded stereoselectivelyto give the trans-anticis ketone-A, M. P. 187. A small proportion of thetrans-antirans ketone-B (described below) was isolated from motherliquors. Ketone-A could also be produced from the enol ether II byallowing the hydrogenation to proceed beyond the dihydro stage (III) toreduce the styrene bond. Acid hydrolysis of the resulting tetrahydroenol ether gave ketone-A. The ultraviolet absorption spectrum of thisketone-x max. 271.5 mu (log 6 3.09), 278.5 (3.13); min. 243.5 (1.98),275.5 (3.04)-is prac tically identical with that of S-methoxytetralinshowing clearly that the styrene bond was indeed reduced.

Reduction of ketone-A either with lithium aluminum hydride or byhydrogenation over platinum oxide pro ceeded stereoselectively yieldingan alcohol, M. P. 132 represented by Formula VIII. This product was alsoformed directly by palladium-catalyzed hydrogenation of 1 methoxy 8hydroxy 10a methyl 5,6,8,9,10,10a, 11,12-octahydrochrysene, M. P. 147,which was obtained by the action of lithium aluminum hydride on thetetracyclic ketone I.

When the A/B-transdihydro ketone IV was converted to the ethylene ketalV, M. P. 112, and this derivative treated With lithium and alcohol inammonia, the 4b,10b- (styrene) double bond was reduced stereoselectivelyto produce VI, M. P. 124", which on acid hydrolysis yielded a tetrahydroketone, M. P. 211, having an ultraviolet spectrum identical to that ofketone-A. This new isomer is the trans-anti-trans ketone-B. Ketone-Bcould also be obtained in somewhat lower yield by lithium-ammoniaalcoholreduction or" the dihydro enol ether III followed by acid hydrolysis. Inthe reduction of the ketal V described above, a small yield of anisomeric tetrahydro ketal, M. P. 138, was isolated, and this on acidhydrolysis yielded ketone-A. When the ketal V was treated with lithiumin ammonia at 150 p. s. i. and 25, then with alcohol at atmosphericpressure, extensive demethylation as well as reduction occurred yieldingthe ketal phenol (Formula V1 with OH in place of OCHs at the 1-position)M. P. 191, which on acid hydrolysis afforded the transanti-transphenolic ketone, M. P. 235

Lithium aluminum hydride reduction of ketone-B proceededstereoselectively to give an alcohol, M. P. 124 and 137, which gave aprecipitate with digitonin and is represented by Formula IX in which thehydroxyl group is ,B-oriented. The best method of preparing this alcoholis by a one-step reduction of the tetracyclic ketone I with sodium orlithium and alcohol in ammonia. The product was conveniently isolated asthe acetate, M. P. 146.

Catalytic hydrogenation of the A/B cis-dihydro ketone Xi over 30%palladium hydroxide-on-strontium carbonate proceeded stereoselectivelyto give a new tetrahydro ketone, M. P. 104, having an ultravioletspectrum identical with that of ketone-A showing that the 4b,10b-(styrene) bond was reduced. The configuration has been proved to becissyn-cis ketone-C. Lithium aluminum hydride reduction of ketone-C gavestereoselectively the corresponding alcohol, M. P. 125, which failed togive a precipitate with digitonin and is assigned the 8stconfiguration.

Conversion of the A/B cis-dihydro ketone XI to the ketal XII, followedby lithium and alcohol in ammonia resulted in reduction of the4b,10b-(styrene) double bond, as shown by ultraviolet spectroscopy, toproduce a mixture of tetrahydro ketals, M. P. and 211. The former(XIII), preponderant isomer on acid hydrolysis yielded a new tetrahydroketone, M. P. 136, which proved to be the cis-anti-trans ketone-D. T ehigher-melting 'ketal, XIV, yielded on hydrolysis another tetrahydroketone, M. P. 174, which is formulated as gave a precipitate with Vpalladium hydroxide on acetyl group offers hindrance preferentially addsto the topside, and the the cis-anti-cis ketone-E, by analogy totheconfiguration of the product formed in lesser amount upon similarreduction of the A/B trans-dihydro ketal V. Both sketones-D and -E hadultraviolet spectra identical with that of ketone-A. Reduction ofketone-E With'lithium aluminurn hydride gave a mixture of Ca epimericalcohols, M. P. 181 and 158. The latter, but not the former, digitoninand the alcohols are accordingly assigned the 8B and 8a configurations,respectively. V

l-methoxy-6a-acetoXy-8-keto-10a methyl 5,6,6a,7,8,

9,10, 10a,11,12-decahydro-chrysene (ml) (cf. W. S. Johnson,;Ser. No.424,505, filed April 20, 1954, and now a abandoned) was hydrogenated inthe presence of 30% strontium carbonate catalyst to compound (XXIII).The large to the approach of the catalyst to the backside of the givethe '4b,l0b-dehydro pound thus has the trans-syn-cis configuration. Fivehours heating of (XPGII) with sodium methoxide gave ketone-F(XX[V).Reduction of ketone-F with lithium and alcohol in liquid ammonia gavethe carbinol (XXV). I To continue the synthesis of the non-aromaticsteroids, 7

the l-alkoxy-S-hydroxy-lOa methyl 4b,5,6,6a,7,8,9,l0,lOa,l0b,'11,12-dodecahydrochrysenes (VIII, IX and other stereoisomers)prepared as described above, are reacted with lithium in the presence ofethanol and liquid ammonia to reduce partially the aromatic ring to givethe correspondinglhexadecahydrochrysenes of the Formulas XVIII or XIX.The remaining double bond is then reduced by catalytic hydrogenation togive an octadecahydrochrysene of the Formula )QC. Chromic oxideoxidation of the latter gives a diketone of the Formula XXI. A specificand preferredaspect of the invention com- 'prises the preparation ofdl-lS-nor-D-homoandrostane- 3,17a-dione (XXI trans-anti trans-anti-transconfiguration) which possesses androgenic activity; assay in rats showedit to be at least one-tenth as active as testosterone.

This represents the first reported totally synthetic androgenicsubstance of any appreciable activity. dl-l8-nor-D-hom0androstan-3fi-ol-17a-one (XX, trans-anti-trans-antitransconfiguration) is also useful as an intermediate in the preparation ofthe naturally occurring androgens, e. g. epiandrosterone. Condensationof XX with furfural, introduction of an angular methyl group in the13-position (of. W. S. Johnson, J. Am. Chem. Soc. 65, 1317 (1943)) V andacetylation: of the 3-hydroxy group gave 'dl-17-furfurylidene-D-homoepiandrosterone acetate (M. P.

192492.5" 'C.; C, 76.19; H, 8.53). Ozonolysis of the latter fcllowed'byesterification with diazomethane afiord ed dl-dimethyl 33-acetoxyetioallobilianate (M. P. l36- 137 C.; C, 68.12; H, 9.29) havingan infrared-spectrum identical with that of the bilianate prepared bydegradation of authentic epiandrosterone, 'Dieckmann cyclization of thebilianate'with potassium tertiary-butoxide, followed by acid hydrolysis,gave dl-epiandrosterone (M. P. l61-162'C.; C, 78.42; .H, 10.49) havingan infrared spectrum androsterone derived from natural sources.

By analogons'procedures, the 3-hydroxy compound 2 corresponding to thecis-anti-tran ketone-D can be reduced-to an octadecahydrochrysene havinga A/B .cisring juncture which is a precursor of the naturally occurringprogestational and cortical hormones. 7 Charts 1, 2 and 3 illustrate bygeneral formulae 'various reactionsreferred to above. r

CHART I.(A/B TRANS SERIES) molecule, thus hydrogen resulting com- 7indistinguishable from that of d-epi a: O O. 5 0

IV VI l. l t 10 1 l I z z t I 1 5 Trans-anti-cis Trans-anti-transketone-A ketone-B Trans-syn-cis ketone F CHAR-T 2.(A/B ors SERIES)Cis-syn-cts ketone-O CHART 3 I VIII, IX, etc.

HO- HO XVIII XIX XX XXI EXAMPLE I hydrochrysene (II) A solution of 49.2g. of tetracyclic ketone I, M. P. 173.5-l75.5 in 250 ml. of dry benzene,25 ml. of absolute ethanol and 49 g. of ethyl orthoformate was confinedto an atmosphere of nitrogen, then 4 ml. of a solution of hydrogenchloride in absolute ethanol was added and the mixture heated underreflux. Two additional 1.5 ml. portions of the alcoholic hydrogenchloride solution were added after 3 hours and then after 8 hours. Afterrefluxing for a total of 22 hours, the mixture was cooled, shaken with15 g. of sodium hydroxide dissolved in dilute alcohol. Water was added(and more benzene if the enol ether began to crystallize), the benzenelayer separated, and the aqueous layer extracted with ether. Thecombined organic layers were washed with saturated sodium bicarbonatesolution, water, and dried over anhydrous magnesium sulfate. The paleyellow solid obtained on removal of the solvent was crystallized from amixture of 115 ml. of benzene and 790 ml. of absolute ethanol containing1 ml. of pyridine. The enol ether crystallized as pale yellow needles,M. P. 133l38.5. This product was satisfactory for the hydrogenation. Asample repeatedly recrystallized from absolute ethanol containing atrace of pyridine was obtained as pale greenish yellow needles, M. P.134-136", A max. 227 111 i (log E 4.58).

Calcd. for C22H26022 C, 81.95; H,8.13. 81.8; H, 8.18.

Found: C,

EYAlX EPLE I1 l-mez'hoxy-8-afizoxy-1 Orr-methyl-5,6,6a,7,10,10a,1 1,12-octahydrochrysene (III) A solution of 39.52 g. of the enol ether (It) in177 m1. of 95% ethanol and 354 ml. of benzene was hydrogenated over 5.0g. of 6% palladium-on-strontium car bonate at room temperature and 30-40p. s. i. The r6- action was interrupted after the calculated amount (forone double bond) of hydrogen was absorbed, the mixture was filtered, andthe filtrate evaporated. The oily residue was dissolved in 400 ml. ofhot absolute ethanol containing a trace of pyridine, and on coolingcrystals separated, M. P. 114120. This material was satisfactory for thenext stage.

Analysis.Calcd. for CzzHzsOz: C, 81.44; H, 8.70. Found: C, 81.2; H,8.69.

EXAMPLE III Trans-1 -meth0xy-8-keto-10a-methyl-5,6,6a,7,8,9,10,10a,]1,12-decahydr0chrysene (1V) T o a boiling solution of 7.95 g. ofdihydro enol ether (III), M. P. 114-119 in 10 ml. of benzene was addedin succession 230 ml. of boiling ethanol, 40 ml. of water, 4.5 ml. of 12N hydrochloric acid, and 35 ml. of water. The mixture was allowed tostand at room temperature for 5 hours, then for 2 hours at 0. The paleyellow crystals which separated were recrystallized from 40 ml. ofn-butyl acetate giving prisms, M. P. 167172. Sublimation at -190" (0.05mm.) gave material, M. P. 168172, of sufiicient purity for hydrogenationto the tetrahydro ketone A. A specimen repeatedly recrystallized fromethyl acetate was obtained as colorless prisms, M. P. 175.5-176", x max.222 mp. (log a 4.49), 265.5 (4.14); A min. 244 (3.88).

Analysis.-Calcd. for C2oH2402: Found: C, 81.2; H, 8.44.

EXAMPLE IV 1 -methoxy-8-acezoxy-l 0a-methyl-5,9,1 0,10a,1 1 ,12-hexahya'roch rysene (XVI) A solution of 0.84 g. of the tetracyclicketone ('I) in 2 ml. of acetic anhydride and 3 ml. of acetyl chloridewas heated under reflux (nitrogen atmosphere) in an oil bath at 95-105for 2 hours. The mixture was cooled, the solvent evaporated at reducedpressure, and the residue recrystallized from absolute ethanol givingcrystals, M. P. 135438". Evaporative distillation at (0.07 mm.) followedby crystallization from absolute ethanol afiorded greenish yellowneedles, M. P. 136.5138.5, A max. 224 my. (log 6 4.61). This materialwas again evaporatively distilled before analysis.

Analysis.-Calcd. for C22H24O3: C, 78.54; H, 7.19. Found: C, 78.4; H,7.12.

EXAMPLE V 1 -methoxy-8f3hydroxy-J Oa-methyl-5,7,8,9,10,10a,11JZ-ocZahydrochrysene (XVII) A solution of 1.00 g. of the enol acetateXVI, M. P. 136-138", in 100 ml. of 95% ethanol was cooled to 5 and addedslowly to a stirred, cooled (ice bath) solution of 2.54 g. of sodiumborohydride in 65 m1. of 75% aqueous ethanol. After the addition wascomplete, 32 ml. of 10% sodium hydroxide solution was added, the mixtureheated under reflux for about 30 minutes, then most of the solvent wasremoved at 60 (12 mm.). The product was taken upin ether, washedthoroughly with water, and dried over anhydrous sodium sulfate. The oilobtained upon evaporation of the solvent was dissolved in 15 ml. of 95%ethanol, 0.3 ml. of concentrated hydrochloric acid was added and themixture boiled under reflux in an atmosphere of nitrogen for 1 hour. Thebrown solution was neutralized with solid potassium carbonate, distilledat 80 (10 turn.) to remove alcohol, and the residue extracted withether. The ether solutions were washed thoroughly with water, dried overanhydrous sodium sulfate and concentrated. The yellow-red oily residuewas crystallized from a concentrated ether solution by cooling in a DryIce-acetone bath. The crystalline product after washing with ether had aM. P. 7275.

The acetate, prepared with isopropenyl acetate and .15 ml. of a solutionof 0.258 M .A solution or 2.434 g.

EXAMPLE vr' Cis 1 methxy-8-ket0-I0a, methyl-5, 15,641,7,8,9,10,I0a,-11,]2,decahydrochrysene (XI) A mixture of 6.00 175-176, 0.10 g. of

g. of the tetracyclic ketone l, M. P. 10% palladium-on-carbon, ml. of95% ethanol, 50ml. of benzene and 1 drop of potassium hydroxide solutionwas agitated with hydrogen at room temperature and atmospheric pressure;In 1 hour the absorption of gas, which was 101% of that calculated (forone double bond), ceased. The mixture was filtered, and the filtrateevaporated leaving crude cis-dihydro ketone, M. P. 117.5-119".Recrystallization from 95% ethanol gave a product, M. P. 119.5-121". Aspecimen which was repeatedly recrystallized from methanol was obtainedas colorless blades, M. P. 123-124.

. Analysis.Calcd. for ,C2nH24Oz, C, 81.04; H, 8.16. .Found: C, 81.1;H,8.52. V a 4 EXAMPLE VII .Trans 1fmethoxy-Sfl-hydroxy-IOa-mezhyl-5,6,6a,7,8,9,-10,10a,[LIZ-decrfhydrachWsene (VII) 7 To an ice cold solution of 0.500g. of the transdihydro -ketone (IV), M. P. 175-178, in ml. of drypurified dioxane and 60 ml. of dry ether was added with swirling lithiumaluminum hydride in ether over a period of 5 minutes. The mixture wasboiledunder refiu xifor labour, 'cooled, lml. of water cautiously added,and the granular precipitate which formed was-'washed by decantationwith ether andgben- -zene.- The organic solutions were dried overanhydrous sodium sulfate, and evaporated. The residue was crystallizedfrom chilled acetone-ether to give colorless prisms, M. P. 86.4-94.8.

Analysis.-Calcd. CaoHzsOz: Found: C, 80.1; H, 8.43.

The alcohol gave a crude digitonide melting at 175-225; The benzoate ofVII prepared from benzoyl chloride and pyridine was crystallized frombenzene-petroleum ether (60-68) giving colorless prisms, M. P. 193.4-

Sublimation at 160 (0.05 mm.) followed by recrystallization gavematerial, M. P. 197.2-200.2. The purest specimen prepared after repeatedrecrystallization melted at 2029-2035". r Analysis.'Calcd. C27H300a:Found: C, 80.8; H, 7.54.

EXAMPLE vnr Cir-1-meth0xy-8a-hydr0xy-]0a-methyl-5,6,6a, 7,8,9

10, 10a, 1],]2-decahydr0chrysene (X) of the cis-dihydro ketone XI, M. P.119.5-120.5 in 20 ml. of dioxane and 70 ml. of ether was reduced with 45ml. of a solution of 0.402 M lithium aluminum hydride in ether by theprocedure dejscribed above for the trans isomer. The crude product had aM. P. 147.3-150.8. Crystallization from benzene- Tpe'tro'leum ether(6068) gave colorless needles, M. P. 156-158 with previous softening.Repeated recrystallization from petroleum ether (60-68") raised theM..P. to 158.5-159.1, A max. 222.5 my (log 6 4.37), 269 (4.06); A min.244.5 (3.71).

Analysis-Calcd. CzoHzsOzt precipitate with digitonin, the

'Found: C, 80.3; H, 8.81.

followed by sublimation at 130 (0.05 mm.) gave small colorless prisms,M. P. 126-1268".

The cis-Sa-hydroxy compound, M. P. l54.3-l55.8 with previous softeningwas also prepared by hydrogenating the cis-dihydro .ketone XI over'platinum oxide in dioxane containing a trace of concentratedhydrochloric acid.

EXAMPLE IX Trans anti cis 1 5 methdxy-S-keto-l0a-methyl-4Ir,5,6, 612,7,8,9,1 0,] 0a,] 05,] I ,1 Z-dodecahydrochrysene (A) A suspension of 3.0g. of 30% palladium hydroxideon-strontium carbonate in 100 ml. ofbenzene and 100 ml. of 95 ethanol was shaken with hydrogen at roomtemperature and 30-40.p. s. i. until no more gas was absorbed (about 12minutes). A solution of 12.16 g; of

sublimed trans-dihydro ketone IV, M. P. 168-172", in

and the shaking 100 ml. of benzene was then added continued at roomtemperature and 30-40 p. s. i. After 2 hours the hydrogenation hadbecome very slow and approximately the calculated amount (for one doublebond) of gas was absorbed. The mixture was filtered, the filtrateevaporatedunder reduced pressure and the colorless crystalline residuerecrystallized from n-butyl acetate. The colorless prisms obtained inthe first crop had a M. P. .183.5-l86.5 (vac.) with previous shrinking.

The specimen of this ketone A, M. P. 166-174 (in an open tube) obtainedby hydrolysis of the ketal was re? crystallized from ethyl acetate andthen sublimed at 170 (0.03 mm.), M. P. about 166-174 (in an open tube)or 186.5-187.5 (vac.) with slight previous shrinking, A max. 271.5 mp.(log 5 3.09), 278.5 (3.13); A min. 243.5 (1.98), 275.5 (3.04). V

Analysis.-Calcd. for CzdHz'zOa: Found: C, 80.7; 'H, 8.77.

After standing for several months the mother liquor from thecrystallization of ketone A deposited a second genation of the enolether II of the tetracyclic ketone W This material failed to give aprecipitate with digitonin; V

J The acetate prepared from acetic anhydride andpyri- .dine was obtainedafter sublimation 'at*130 (0.05 mm.),

P; 129-134 1 Repeated recrystallization. from acetone (I) as describedabove to proceed further to the tetrahydro stage. Hydrogenation of the'dihydro enol ether III, over palladium-on-strontium carbonate similarlygave after recrystallization from ethyl acetate, ketone A, M. P. 168-l78(open tube).

The ethylene .ketal. of ketone-A was prepared from 0.72 g. of ketone,0.04 g. of p-toluenesulfonic acid monohydrate in 40 ml. of dry toluene,and 6.5 ml. of ethylene glycol. The mixture was heated so that slowdistillation .occurred' over a 7-hour period during which fresh toluenewas added to maintain the original volume. A total of ml. of distillatewas collected. The mixture was allowed to cool, washed several timeswith saturated so- .dium bicarbonate solution, and thenwith Water. The

aqueous layers were extracted with ether, and the combined organiclayers dried over anhydrous magnesium sulfate. The colorless crystallineproduct. remaining after removal of the solvents at reduced pressure wascrystallized from methanol-acetone to give the ketal, M. P. 131-1335".Two recrystallizations from methanol acetone gave long-colorless blades,M. 'P. 1355-1375, A max. 270 my log 53.12), 278.5 (3.14); A min. 243.5(2.19), 275.5 (3.06).- V i i Analysis.Calcd. for CzzHaoOs: c, 77.15;8.83.

Found: C, 76.82; H, 8.71.

EXAMPLE X Trans anti-cis-I-methoxy-8fl-hydroxy l0a-methyl-4b,5,6,

-6a,7,8,9,10,10a,101),]1,]2-d0decahydr0chrysene (VIII) 'Aimixture of3.00 g. of the tetrahydro ketone-A and 30 ml. of dry benzene was warmedto efiectdissolution,

C, 80.49; H, 8.78. V

then 100 ml. of dry purified dioxane and 150 ml. of dry ether wereadded. A solution of 2.7 g. of lithium aluminum hydride in 100 ml. ofdry ether was then added slowly with stirring over a 45-minute period.After the addition, the mixture was heated under reflux for 4.5 hoursand allowed to stand overnight at room temperature. Dilute sulfuric acid(8 ml. of concentrated acid in 200 ml. of water) was added cautiously,the layers separated, the aqueous portion extracted with ether, and thecombined organic layers dried over anhydrous magnesium sulfate. The oilyresidue obtained on removal of the solvent at reduced pressure wascrystallized from benzenepetroleum ether (100) to yield the carbinol, M.P. 132- 134. Repeated recrystallization gave colorless blades, M. P.130.5-132.5, A max. 271 m (log 6 3.14), 278 (3.15); l. min. 243.5(2.05), 275 (3.10).

Analysis.-Calcd. for C20H28O2: C, 79.95; H, 9.39. Found: C, 80.2; H,9.44.

This substance gave only atrace of a precipitate with digitonin.

The acetate, prepared with acetic anhydride and potassium acetate inacetic acid, crystallized from dilute ethanol in the form of colorlessblades, M. P. 109-109.5. Two additional recrystallizations raised the M.P. to 109.5-110".

Analysis.--Calcd. for C22H30032 Found: C, 77.6; H, 8.83.

Catalytic hydrogenation of 1.00 g. of the tetrahydroltetone in 20 ml. of95 ethanol and 40 ml. of benzene over 0.20 g. of platinum oxideproceeded to completion calculated amount of gas absorbed) in 70 minutesat room temperature and 30-40 p. s. i. Crystallization of the productfrom benzene-petroleum ether (100) gave the carbinol VIII, M. P.135-136", undepressed on admixture with the product described above.

EXAMPLE XI 1-meth0xy-8-hydr0xy-1 a-methyl-5,6,8,9,10,10a,11 ,12-octahydrochrysene A solution of 2.00 g. of the tetracyclic ketone I, M.P. 169.7-172.2 in 40 ml. of dioxane and 150 ml. of ether was reducedwith 0.01 mole of lithium aluminum hydride in 25 ml. of ether. Theprocedure was essentially the same as that described above for thereduction of the trans-dihydro ketone to VIII. After crystallizationfrom acetone-petroleum ether (60-68) the product had a M. P.150.4-154.2. Recrystallization of this material from aqueous ethanolgave plates which melted and resolidified between 100 and 110, thenremelted at 140.5- 142.5. Occasionally a form, M. P. 138-145 wasobtained from acetone-petroleum ether. Repeated recrystallization fromaqueous ethanol gave small colorless plates which after drying for 20hours at 55 (0.05 mm.) melted at 146.5-147", max. 222 mp (log 6 4.37),268.5 (4.06); A min. 244 (3.67).

Analysis.-Calcd. for Gaol-124.02: Found: C, 81.0; H, 8.38.

EXAMPLE XII Hydrogenation of 1 -methoxy-8-hydr0xy-1 Oa-methyl-5,6,8,9,10,10a,1 1 ,12-0ctahydr0chrysene A solution of 1.182 g. of thecarbinol of Example XI, M. P. 147.6151.1, in 50 ml. of 95% ethanol wastreated with 5% palladium-on-carbon catalyst and the mixture allowed tostand overnight. The catalyst was removed by filtration, and thefiltrate shaken with hydrogen at room temperature and atmosphericpressure in the presence of 0.355 g. of 6% palladium-on-strontiumcarbonate. After 2 hours the calculated (for two double bonds) amount ofhydrogen was absorbed, and the reaction was interrupted. The mixture wasfiltered, the filtrate evaporated, and the residue crystallized fromchilled acetone ether to give colorless needles, M. P. l25.4-128.8.Repeated recrystallization from acetone-petroleum ether (60-68") andsublimation at 130 (0.05 mm.) gave material, M. P. 1288-1325",undepressed on admixture with trans-anti-cis-tetrahydro carbinol VIII,M. P. 132- 134, described above. The 128.8-132.5 compound had A max.270.5 m (log 6 3.08), 278 (3.10); A min. 243.5 (2.03).

Analysis.-Calcd. for C20H2s02: C, 79.95; H, 9.41. Found: C, 79.9; H,9.32.

EXAMPLE XIII Trans-1 eneth0xy-8-ethylenedioxy-10a-methyl-5,6,6a,-7,8,9,1 0,1 0a,] 1 ,1 Z-decahydrochrysene (V) A solution of 22.7 g. ofthe trans-dihydro ketone IV, M. P. 167-172" and 1.2 g. ofp-toluenesulfonic acid monohydrate in 1.2 l. of dry toluene and 200 ml.of ethylene glycol was boiled under reflux with an arrangement forpartial take-01f. During 4 hours, 400 ml. of distillate was collected,then an additional 50 ml. of ethylene glycol and p-toluenesulfonic acidwere introduced. Refluxing was continued for 4 hours more during which200 ml. of distillate was collected. The product was isolated asdescribed above for the ethylene ketal of ketone A. The crude productwas crystallized from a mixture of 15 ml. of acetone and 250 ml. ofmethanol to yield colorless needles, M. P. 110-111. On repeatedrecrystallization of a sample from another run, the M. P. was111.5-112".

Analysis.-Calcd. for C22H23O3: C, 77.61; H, 8.29. Found: C, 77.6; H,8.09.

The ethylene ketal V was also prepared directly from the dihydro enolether III by reacting 25.62 g. of the latter, M. P. 116-120", and 1.60g. of p-toluenesulfonic acid monohydrate in 950 ml. of dry toluene and200 ml. of ethylene glycol. After a total of 21 hours of refluxing (0.4g. additional acid being added after 17 hours), and crystallization fromacetone-methanol, the ketal was obtained, M. P. -1075".

EXAMPLE XIV Trans anti trans 1 methoxy 8 ethylenedioxy 10amethyl4b,5,6,6a,7,8,9,10,10a,10b,11,12-d0decahydr0- chrysene (VI) A solutionof 3.40 g. of the trans-dihydro ketal V, M. P. -111, in 300 ml. of dryether was placed in a 1 l. three-necked flask equipped with a sealedwire stirrer, a Dry Ice condenser capped with a soda lime drying tube,and a stopcock sealed to the bottom for draining the flask. The thirdneck was kept stoppered except when reagents were added. Liquid ammonia(400 ml.) was added rapidly, stirring was started (cautiously at first),the 3.40 g. of lithium wire cut into small (1-2 cm.) p eces was added tothe homogeneous solution. A few pieces were first added; then when thesolution became completely blue, the remainder was added as fast aspossible without loss of liquid through the condenser. After theaddition was complete stirring was continued for 15 minutes, then thereaction mixture was drained in a 2 l. beaker containing 33 ml. ofabsolute ethanol, and the mixture was stirred until all of the bluecolor disappeared. The ammonia was evaporated by gentle warming on asteam bath.

The above procedure was repeated 10 times, and the residues remainingafter evaporation of the ammonia were combined. Water was added, theother layer separated, and the aqueous layer extracted twice with ether.The combined ether solutions were washed with water until neutral, anddried over anhydrous magnesium sulfate. The residue obtained uponevaporation of the solvent was recrystallized from a mixture of 375 ml.of acetone and 750 ml. of methanol containing a few drops of pyridine.The first crop was colorless blades, M. P. 123-124". The mother liquorupon chilling deposited a second crop, M. P. 121.5122.5.

Repeated recrystallization gave colorless prisms, M. P. l23.5-124.5.

I Analysis-Calm. for CzzHaqOg: Found; C, 77.2; H, 8.81.

EXAMPLEXV Traris-anti-trans-I -methxy-8-kezf0-1 0a-me!hyl-4b,5,6,6a,

7,8,9,10,I0a,10b,. Ll2-dodecahydrochrysene (B) V (a) FROMIDHE KETAL To asolution of 23.17 g. of theketal VI, in 460 ml. of boiling 95% ethanol.was added 38 ml. of water, followed by a solution of 2.6 ml. ofconcentrated hydrochloric' acidin 20 ml. ,of 95% ethanol, .then finallyan additional 20 ml. of water. Crystallization began within l minute,and the mixture was allowed to stand at room temperature for hours, thenat' 0 for 3 hours.

The yield of ketone B of sufiicient purity for reduction to the alcohol,was 19.53 g., M. P. 204.5-206. A specimen, after two recrystallizationsfrom n-butyl acetate followed by sublimation at 180 (0.01 mm.) wasobtained as colorless prisms. It melted at 2112ll.5 (vac.) with previoussoftening and rehardening-at about 207 sug- V 3.24 g. of lithium and 37ml. of ethanol, there was obtained upon crystallization of-the oilyproduct from absolute ethanol '(trace of pyridine), the trans-anti-transtetrahydroenol ether, M. P. 104-108". This material was employed for thehydrolysis described below. Material of this quality on repeatedrecrystallization from methanolbenzehe' (trace of pyridine) melted .atns-119.

A solution of 1.69 g. of the tetrahydroenol ether, M. P. 104-108",described above in 45 ml. of boiling 95 ethanol was treated with 5.5 ml.of waterfollowed by 0.9 ml. of concentrated hydrochloric acid. Afterstanding for 3 hours at room temperature and overnight at 0, acrystalline precipitate, M. P. l96.5202.5 was obtained.Recrystallization from n-butyl acetate gave ketone-B, M. P. 2035-2065".

EXAMPLE XVI T rails anti trans 1 mellzoxy 85 hydroxy 1 0a methyl4b,5,6,6a,7,8,9,1 0,] 0511017,] 1,12 dodecahydro- V chrysene (IX) Asolution of 25.9 g. of lithium aluminum hydride in 680 ml. of dry etherwas added over a 30-minute period to a stirred, refluxing suspension offinely powdered ketone B, M. P. 204.5206, in.300 ml. of dry dioxane, 300ml. of dry ether and 100 ml. of dry benzene. The mixture was heatedunder reflux for 5 hours, cooled, ethyl acetate added to decompose theexcess lithium aluminm hydride, then a solution of 78 ml. ofconcentrated sulfuric acid in 1 l. of water was cautiously added. Theaqueous layer was extracted with ether, and the combined ether solutionswere washed with saturated sodium bicarbonate solution, with water, anddried over anhydrous magnesium sulfate. The residue remaining uponevaporation of the solvent at reduced pressure was crystallized from 180ml. of .pe

' troleum ether (100) containing a trace of ethyl acetate to yield aproduct, M. P. 1175-122". This substance exsists in two polymorphic forms, Thus when the above material was recrystallized from ethylacetate-petroleum ether (-68") a material, M. P. 136.3-137", wasobtained. In another similar run a material, colorlessneedles, M.P.=1.23.5124.5, was obtained after three recrystallizations frombenzene-petroleum ether (6068).

. rated and the residue dried in vacuo to 12 Analysis- {Calcd forgCzoHzsQzi C, 79,95,1 1, 9.39. Found: 'C, .8.0- 9-43- On 'standing, thelower-melting form the higher-melting modifications. ,Both forms havegiven the sameacetatedescribed below. The acetate-prepared with aceticanhydride and potassium'acetate in acetic acid, was obtained ascolorless.

prisms, P. 15051505". (soft at 149) after recrystal lizationfrornaqueous ethanol and sublimation at 140150 (0.03 min).

Analysis-Calm. for CzzH'aoOs:

Found: C, 7.6.8; H, 8,56.

EXAMPLE XVII Trans cis 1 methoxy 6a 'acetoxy" 8 keto 10a methyl 4b,5,,6a,7,8,9,10,l0a,10b,]1,12-d0decahydrochrysene (XXIII) in a 450 ml.bottle 4.630 g. of1-methoxy 6a-aceto;ry-8- l eto --10a methyl5,6,6a,7,8,9,10,10a,l1,12 decahydrochrysene (XXII), M. P. 1455-1465",was dissolved in 200 ml. of 'hot'ethanol. After cooling to roomtemperature, 1.5 g. of 30% palladium hydroxide on strontium carbonatewas added and hydrogenation carried out at 2-3 atmospheres by shaking.The hydrogen uptake the first'2 minutes was accounted to the catalystand the solvent. After 20 hours the hydrogen uptake was 114% of thetheoretical 'one moleandthe reaction was stopped at this point Thecatalyst was removed by filtration and washed p with hot benzene sincesome of the product had crystalhad been evaporated in a current lized.'After the solvent of air, the residue was dissolved in benzene,filtered again, and the benzene evaporated. The residue was dissolved inhot ethanol and allowed to cool yielding XXIII, M. P. 7 177-181 EXAMPLEXVIII Trans syn cz 's 1 me th oxyf- 8 keto 10a methyl -4b,- 5,6,6a,7,8,9,10,10a,10b,11,12 dodecahydrochrysene (XXIV) -In a 1 .l.round-bottomed flask 7 g. of sodium was allowed to react with 750 ml. ofanhydrous methanol after which a solution I XXIII, M. P. 173180', in ml.of dry benzene was added. The mixture was refluxed 5 hours at whichtime. it was colored orange. Acetic acid was added dropwise until thecolor changed abruptly to yellow and most of the solvent .Was removedunder reduced pressure. After water and benzene'were added to theresidue, the layers were separated and the aqueous layer extracted threetimes with ether. The combined organic layers were washed with saturatedsodium chloride solution. After drying over anhydrous magnesium sulfate,the solvent was evapoleave a yellow solid,'M. P. 132-144".Recrystallization from ethanol gave XXIV, M. P. 148150,and a secondcrop, M. P;

A lower melting polymorphic form of XXIV was sometimes obtained ashexagons, M. P. The high melting form' usually crystallized as large,irregular, colorless prisms, but also sometimes as large cubes orleaflets. Repeated recrystallization from ethanol gave M. P. 150- 151";A max. 232 III/.4 (log 6 4.27); 240 (4.26), 278 (3.30); A min. 236(4.25), 275 (3.27).

Analysis.+Calcd. for Gaol-12402: C, 81.04; H, 8.16. Found: C,.80.87; H,8.31.

EXAMPLE XIX To a 2 1. 3-necked flask containing 1200 ml. of liquidammonia was added 4.00 g. of ketone' XXIV, 'M. P. l49-15-l, dissolved in100ml. of absolute ethanol.

While the mixture was being stirred, 2.5 g. of lithium changes over to Vof 17.80 g. of the 6a-acetoxy compoundv wire was added in a 2-3 minuteperiod during which a deep blue color developed. An additional g. oflithium wire was added over a 20 minute period. Stirring was continuedan additional minutes at the end of which the blue color haddisappeared. Ether was added slowly and the ammonia allowed to boil awayby warming the reaction flask first in water and then on a steam-bath.When the ammonia was gone, 500 ml. of water was added and the layersseparated. After extracting the aqueous layer three times with ether,the combined ether layers were washed with saturated sodium chloridesolution and dried over anhydrous sodium sulfate. The ether was removedby distillation to leave a red oil. The red oil was heated 3 hours on asteam-bath with 50 ml. of isopropenyl acetate and 0.1 g. ofp-toluenesulfonic acid monohydrate. After isolating the product by theabove procedure, there was obtained from ethanol XXV acetate, M. P.130-132", as orange crystals and a second crop, M. P. 128-130".

In an experiment similar to the one described above, 0.500 g. (1.69moles) of ketone XXIV, M. P. 148-149", was reduced to the alcohol XXV by1.7 g. of lithium in 200 ml. of liquid ammonia and ml. of absoluteethanol. There was isolated an oil which was chromatographed on 12 g. ofalumina. When the column was eluted with benzene, there was obtained0.025 g. of oily material. When the column was eluted with 1:24chloroform: benzene, there was obtained 0.015 g. of ketone XXlV, M. P.156-163". When the column was eluted with 1:1 chloroformzbenzene, therewas obtained 0.443 g. of alcohol XXXV, M. P. 140-143".

EXAMPLE XX Cis syn cis 1 methoxy 8 keto 10a methyl-4b,5,6,6a,7,8,9,10,10a,10b,11,12 dodecahydrochrysene A solution of 2.25g. of the cis-dihydroketone XI, M. P. 119.5-121" in 30 ml. of 95%ethanol and 30 ml. of benzene was hydrogenated over 0.50 g. of 30%palladium hydroxide-on-strontium carbonate at room temperature andatmospheric pressure. The uptake stopped after 2 hours, 96% of thecalculated amount of gas being absorbed. The mixture was filtered, andthe filtrate evaporated to give a residue, M. P. 76-92".Recrystallization of the material from 95% ethanol gave ketone-C, M. P.97-102", A max. 271 (log 6 3.16), 278 (3.19); 8 min. 244 (2.37); 275(3.13). Comparable material from another run was recrystallized frompetroleum ether (60-68"), then from methanol to give colorless prisms,M. P. 103-105".

Analysis.Calcd. for C20H2602Z C, 80.49; H, 8.78. Found: C, 80.2; H,8.96.

The semicarbazone was obtained from absolute ethanol as colorlessmicrocrystals, M. P. 217-219" (dec.).

Analysis.-Calcd. for C2lH2902N3Z C, 70.95; H, 8.22. Found: C, 70.6; H,8.28.

EXAMPLE XXI Cis-syu-cz's-I -methoxy-8u-hydr0xy-1 0a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,11,IZ-dodecahydrochrysene A solution of 0.725 g. ofketone-C, M. P. 97-102", in ml. of dioxane, 10 ml. of benzene and 50 ml.of ether was treated with 10 ml. of 1 M lithium aluminum hydride asdescribed above for the preparation of the trans-anti-trans-8fi-hydroxycompound (IX) except that the mixture was refluxed for only minutes. Asolution of the crude product was adsorbed on a column of activatedalumina (20 g.). Recrystallization of the fraction which was eluted with2:3 chloroform-benzene, from petroleum ether (60-68") gave the carbinol,M. P. 123-125".

14 EXAMPLE XXII C is-l-meth0xy-8-ethylenedi0xy-10a-methyl-5,6,6a,7,8,9,1 0, l 0a,11 ,1Z-decahydrochrysene (X I I A mixture of 1.00 g. of the cis-dihydroketone XI, M. P. 117-119", 9 ml. of ethylene glycol, 50 ml. of tolueneand 0.04 g. of p-toluenesulfonic acid monohydrate was slowly distilled.Each time 10 ml. of distillate was collected, 10 ml. of fresh toluenewas added to the reaction mixture, and this process was continued for 4hours. Then 1 ml. of ethylene glycol and about 10 mg. of acid catalystwere added, and the distillation operations continued for an additional2 hours. The product was isolated as described above for the ketal ofketone A. The crude oily product was evaporatively distilled at 0.01 mm.After a forerun of 0.10 g. collected at -130", the desired product wasobtained at -150".

Analysis.-Calcd. for CzzHzaOs: C, 77.61; H, 8.28. Found: C, 77.9; H,8.28.

EXAMPLE )CGII Lithium reduction of the cis-dihydro ketal (XII)Approximately 220 ml. of ammonia was added carefully to a solution of2.23 g. of the ketal (produced as described above) in 210 ml. ofanhydrous ether. Lithium wire (0.190 g.) was added with stirring, andafter dissolution was complete the dark green-colored solution wasstirred for 20 minutes, then an excess absolute ethanol was addeddropwise, and the ammonia evaporated by warming. The mixture was dilutedwith water, the aqueous portion extracted with chloroform, and thecombined organic layer dried over anhydrous sodium sulfate. The residueobtained upon evaporation of the solvent was crystallized from ethylacetate to give cis-anti-cis-lmethoxy 8 ethylenedioxy 10a methyl4b,5,6,6a,7, 8,9,l0,10a,10b,11,12-dodecahydrochrysene (XIV), M. P.209-211". Recrystallization from ethyl acetate gave colorless blades, M.P. 211.5-212". This material sublimed readily at (0.01 mm.).

Analysis.-Calcd. for C22H3003: Found: C, 77.6; H, 8.87.

The mother liquor from the 209-211" material was evaporated and theresidue crystallized from petroleum ether (60-68") givingcis-anti-trans-l-methoxy-S-ethylenedioxy 10a methyl4b,5,6,6a,7,8,9,l0,10a,10b,11, IZ-dodecahydrochrysene (XIII), M. P.108-110". Repeated recrystallization gave colorless prisms, M. P.110.2-110.8".

Analysis.-Calcd. for CzzHsoOs: C, 77.15; H, 8.83. Found: C, 77.4; H,8.78.

EXAMPLE XXIV Cis-anti-cis-J-methoxy-S-keto 10a methyl 4b,5,6,6a,7,8,9,10,10a,1 1,12-d0decahydr0chrysene (E) A mixture of 0.250 g. of theketal XIV, M. P. 210-212, 10 ml. of dry acetone, and a few crystals ofp-toluenesulfonic acid monohydrate was heated for 4 hours on the steambath. Water was added dropwise to the point of incipient cloudiness. Thecrystals obtained on cooling had a M. P. 171-173". A specimen wasrecrystallized twice from 95% ethanol to give colorless needles, M. P.173.5174.5, Amax. 271 my (legs 3.20), 278.5 (3.20); Main. 244 (2.20,275.5 (3.15).

Analysis.-Cald. for CzoHasO-z: C, 80.49; H, 8.78. Found: C, 80.5; H,8.58.

EXAMPLE XXV Hydrolysis of the cz's-anti-trans-tetrahydro ketal X111) Aspecimen of the ketal, M. P. 1102-1108", was hydrolyzed under theconditions described above. After recrystallization frombenzene-petroleum ether the product ketone-D melted at 134-136".

- 155.7", Amax; 272 m V a surface area as possible;

I EXAMPLE XXVI 7 Cis onti 4 cis- I methoxy 8 hydfoxy methyl4b,5,6,6a,7,8,9,10,10a,10b,11,12-d0decahydr0chrysene A solution of 0.20g. of ketone E, M. P. 173-174, in 10 ml. of dioxane acid ml. of etherwas treated with a solution of 0.06 g. of lithium aluminum hydride in 4ml. of ether. The mixture was heated under reflux for 1 hour, and theproduct isolated essentially as described above for the trans-dihydrocompound (VII); Repeated recrystallization of the crude product frombenzeneie: troleum ether (SO-68) and from ethanol eventually gave.material melting at 176-180". After sublimation inhigh vacuum itwasobtained as colorless microcrystals, M. P; l78181. On treatment withdigitonin it did not form an .appreciable precipitate, and the compoundis accordingly assigned the Swhydroxy configuration.

Analysis-Calm. for CzoHzsOz: C,' 79.95; H, 9.39. 'Found: 'C, 79.7; H,9.33.

From the more soluble fractions in the crystallization of the 176-180material, a second isomer was isolated as colorless prisms, M. P.-157.6158.2, after repeated recrystallization from benzene-petroleumether (60-68 On treatment with digitonin, a noticeable precipitateformed. 'Ihe'compound is therefore assigned the 8/3- hydroxyconfiguration. I

Analysis-Calm. for Gaol-12802: Found: C, 79.9; H, 9.45;

When the carbonyl group of ketone E was reduced withhydrogen overplatinum oxide in 95% alcohol containing a trace of acetic acid,acomparable mixture of carbinols was produced. v

EXAMPLE 7 Cis antit rans 1 met hoxy 8oz hydroxy 1 O-methyl- 4b,5,6,6a,7,8,9,I 0,10a,10b,11,1'2 dodecahydrqchrysene Toa solution of1.700 g. of the cis-dihydrO-Sa-hydroxy compound'X, M. P.'156 -158,described above, in 200 ml. of .dry ether,.was added 256 ml. of liquidammonia followed by 0.184 g. of lithium wire.. The mixture was stirredfor 15 minutes, then anhydrous ethanol was added slowly until the bluecolor disappeared. The ammonia and ether were evaporated on the steambath, ice water was added, and the solid taken up in benzene. The ben-.

zene solution was washed with water, 5% hydrochloric acid and saturatedbrine; The residue obtained on evaporation of the solvent wascrystallized frombenz enerpetroleum ether (60-68) to give colorlessneedlesfM. P. ISO-152. Repeated 'recrystallization frombenzene-petroleum ether (60-68) and" from acetone-petroleum ether(60-68") gave colorless needles, M. P. 155.2-

(loge 3.13), 278 (313); Amin. 244.5 (2.20), 275 (3.07).

EXAMPLE XXVIII hydroxy 10a methyl 4b ,'5,6,6ll,7,8,9,10,I0a,10b,I],IZ-dodecahydrochrysene (IX) '1 suspension was stirredvigorously using a large Hershberg stirrer, and 46 gms. of sodium metalwas added slowly, in

small portions which had been pressed'out to have as big After thefirstfew pieces of sodium 'had reacted vigorously, the "reaction mixturebecame intensely blue on further additions. of the metal; when the bluecolor disappeared, it was noticed that all of the material was now insolution; When all of the sodium had been added, and the last of-theblue color had disappeared, the ammonia was-removed from the stirred 7solution by warming on a steam-bath under a stream Of V (B. P. 60-68).The

ether, and allowed to stand at room temperature. The

solid which separated was removed, washed with a little ether, thefiltrate concentrated, allowed to crystallize and the process repeateduntil no more'solid separated from the mother-liquors.- In this manner,several fractions were collected including a' colorless fraction with aM. P. 124-129. About 2 gms. of this methoxy alcohol (IX) containingfraction. was dissolved in 6 ccs. of dry benzene, diluted with 30 ccs.of light petroleum .(B. P 60-68f),'and placed on a 60 gm. column ofactivated magnesium silicate (Florisil) made up in light petroleum (B.P. 60-68"). Elntion with benzene-light petroleum (1:3) to (1:1) gave 6oily'fractions and elutionwith benzene-light petroleum (3:1) gave 8additional fractions including fraction 7 with a M. P. 125-131" andfraction 10 with a M. P. 129-130. 'Fraction 10 was crystallized fromethyl acetate-light petroleum (B. P. 6 0-68) and the methoxy alcohol(IX) was obtained as an amorphous solid, M. P. 128-130". Sublimationunder high vacuum at .100" gave a sample in the form of colorlessprisms, M. P. 130-132, a

Metholcy a lcohol (IX) acetate acetate (15 ccs.) containingconcentratedsulfuric add (one drop) for two hours. After cooling, the solution .waspoured into saturatedaqueous sodiumbicarbonate,

extracted with benzene, and the-solvent removed under reduced pressurefrom the washed and dried extract. 'The residual brownish oilcrystallized partially on standing: it was dissolved in dry benzenepetroleum (B. P. 60-68", 2 ccs.) and placed 'on a column of neutralalumina (4 gms.) made up in light petroleum following fractions werecollected:

. M.' P., degrees (1) Benzene-light petroleum (13.. P. 60-68") (1:1), 50ccs., 62.9 mgms 143-148 (2) Benzene-light petroleum (B. P. 60-68) (1:1),50 ccs.,11.0 mgms 144-148 (3) Benzene-light petroleum (B. P. 60-68") 7(151), 50 ccs., 3.2 mgms 146-149 ('4) Benzene-light petroleum (B. P.60-68") (3:1); 50 ccs., 2.5 mgms 146-149 V were sublimed at f136/highvacuum (M. P. 149-151, with slight softening at.147) and thencrystallized from ethanol. Thedesired acetate product was obtained witha M. P. of about 149-150.5. It can be hydrolyzed in boiling ethanolcontaining aqueous KOH to pure compound (IX). 7 t I (B) About1000 mgms.of the tetracyclic ketone (I), M; P. 174-176, in drypurifieddioxan' (25ccs.) was added carefully to liquid'ammonia(400 ccs.) containing ethanol(35 ccs., commercial absolute). .To the stirred 'mixture, sodium (6.3gms.) was added slowly in small pieces to maintain a blue solutio i 7 At,the end of the reaction, the product was isolated The. .combined solidswith chloroform, and the resultant yellowish oil crystali ized-oncooling. iThe solid, after washingwith ether, showed M. P. 121-1251 Asmall amount of material insoluble in'a large volume'of' ether(presumably a .less prisms, M. P. 126-127.

c In a similar process to .that'described jin (B) (2 ccs.), diluted withlight dimeric reductionproduct);was removed by filtration, V

i 7 above, the isolated crude yellow .productiwas crystallized byswirling with ether. Sublimation at l.l2"./ high-.vacuum followed bycrystallization'from; light petroleum '(B: P; 90.100-").gave..the.desired methoxy. alcohol. (IX) as colorless prisms, .M. P. 121-128".

' EXAMPLEX'XIX dl 18 nor D homo 13(14) androsten 3B Ol- 1 17a one(XVIII) and dl 18 -110; D-- homo-16(17)- androsten 3B ol 17a -.0ne (XIX)About 1000.1ngms. of themethoxyalcohol (IX), M.- P. 124-125 dissolvedzincommercial absolute ethanol (130 ccs.) wasadded cautiously-to.liquidammonia (150 ccs.) contained: in awide-neckedone-l. flask. -Withvigorousstirring, lithium. wire (10 gms.) was added slowly,

insmallportions. The. wire became coated immediately witha-bronze-coloredliquid-Which was dispersed rapidly throughout the;mixture as small globules, and'the mixture assumed a-v uniformdull-browncolor. At: the-end ofethe-v addition of the metal,:ethanoL wasadded \toremove 1 a paleviscous .oil. This. oil was dissolved .indry-benzene (10 ccs.),, diluted with light petroleum .(B. P.. 60,68

and placedcn a: column of. activated magnesium silicate (Florisil) (40gms.) made up ;inlight petroleum (,B..,P.

60-68 The major fractionsfrorn thecolurnntincluded the following:

Eluting Solvent Fraction Volume, Product No. ccs.

PureBenzene 8l6, incl-.. 2,'5Q0 M. P. 12;125. Benzene-10% ether to Ben-1719, incl 750- -nn-ketonic,- oil. Zena-50% other. Pure ether. 20 20!).911. D 21 200 Oil. .2228, incL v 2, 150. on.

The fractions: 816- inclusive. were-crystallized from light petroleum=(B. P.n901 00): colorlessypl isma tic sublimation at. l30/high vacuumand recrystallization from the same solvent yielded the 13:14 dehydro ketone XVIII as. colorless elongated hexagonal prisms, M-. '.P.l6-3.5-l65.

From fractions-20 and 21 was isolated a furtherquantity ofthe sameketone (XVIII).. Concentrationofihe mother-liquors yielded a colorless.oil showing vise-225 which crystallized on leaving with ether.Sublimation at 1Z5/high vacuum followed by, crystallization fromdiisopropyl ether yielded the ketone (XlX) as colorless rods, M. P.138-139". In -chrysene.--nomenclature XV'III is trans anti trans r1jketo 8 -hydroxy 10a,- methyl- 1,2,3,4,4b,5,6,621,7,8,9,1O,l0a,1.0b,ll,-12 hexadccahydrm chrysene andXlXis .trans anti trans 1 =-keto.- 8 hydroxy 10a methyl1,4,4a,4b,5,6,6a;7,8,9 ,lO,.l0a,-l0b, l l, 12 lZa-hexadecahydrochrysene.

EXAMPLE XXX Direct conversion of the tetracyclz'c ketone (I)..to th e13:14 dehydro ketone (XVIII) and 16:17 dehydro ketone (XIX) i8 purifieddioxan and ethanol (one 1., commercial absolute) was added carefully to3 l. of-liquid ammonia stirred with a large Hershberg stirrer driven byan airmOtOl-,=C0ntfli116d in a 12-1. round bottomed wide-necked blueonly in streaks around the undissol-vedmetal. During thefirsttwenty-five minutes, four meters of wire were added:. after theaddition of more ethanol ccs.), theappearance of bronze-red globules wasnoticed on the. surface of the still 'blue-fieckedmixture asmore lithiumwas added. The tenth meterhad been added after forty-five minutes,followed by ethanol (100 ccs.), and again ethanol (200 ccs.) after thefourteenth meter at the end of one hour. Liquid ammonia (one 1.) andethanol (100 ccs.) were added with the twentieth meter ateighty minutesfrom the beginning ofthe reaction, and ethanol (100 ccs.) again afterthe twenty-third meter (ninety minutes).

:Furth'er liquid ammonia (one 1.) was added with the twenty-eighthmeter'after minutes, and again (one 1.) plusethanol 200 ccs.) after thethirty-second meter (170 minutes). The forty-ninth meter, together withethanol (100 ccs.), was added minutes-from'the start of the reduction.Under these conditions, the reaction mixture remains3.11:6Vfi11'zd11lib1'QDZ6 color: throughout the reaction from the fifthmeter onwards.

The reaction mixture was then left to stir until most of the lithium haddisappeared, additional ammonia (one 1.) being; added to prevent theliquid from becoming too viscous. Finally, ethanol (500 ccs.) was addedto remove any unreacted lithium, and the ammonia was allowed toevaporate from. the stirred mixture-under, a rapid'stream of nitrogen.Water (2-1.) was then added slowly. to. dissolve the solid lithiumethoxide, and the product isolated by thorough extraction with.chloroform. The removalof solvent from the washed and dried solutiongave a viscous, redoil, which showed only endabsorption in theultra-violet spectrum.

This'oil was heated under refluxin ethanol (200 ccs., commercialabsolute) containing aqueous hydrochloric acid (8%, 3O ccs.) for onehour in an atmosphere of nitrogen. After removing most of the ethanolunder reducedpressure at 20, water was added,. and: the organic-materialextracted with. chloroform. Q Afterwashing and drying the productwasisolated as a dark-red glass.

The glass was .next dissolved in dry benzene (1'50 ccs.), diluted with.light petroleum (B. 'P. 6068, 50 ccs.) and placed on. a column ofactivated magnesium silicate (Flonisil) (600.gms.) made upin lightpetroleum (B. P. 60-;68"). The major fractions collected included thefollowing:

Eluting Solvent Fraction No. Vo1ume,l. Properties 14-17 inclusive 4 1824inclusive, 7 25-27 inclusive 4 28-37 inclusive Benzene-40% ether Redoil.

7 Do, Pale .yellow oil. Benzene 20% ether" Oil, crystallized.Benzene-20% ether D0.

to. Benzene Pure ether.

conditionsused-by Reichstein, Helv. Chim. -Acta-19, 11-07 (1936), in theseparation of theadrenal cortical hormones. No pure materialwas;isolated by these procedures but they may be used to advantage whendealing with large scale reductions in order to decrease the amount ofmaterial to be chromatographed.

(B) This reduction was run under the same conditions as that recorded in(A) above except that the concentration of ammonia was controlledthroughout the reaction a so that, although the bronze phase waspresent, the mixture always verged upon theblue also (this was achievedby the cautious addition of ethanol at frequent intervals to prevent theblue color from becoming pronounced).

The isolation and hydrolysis of the crude. .reduction. product werecarried out as described above. The hydrolyzed material was a muchlighter-red oil and, on dissolution in ether (50 ccs.) and leaving at 0yielded a further quantity of material on concentration and leaving at 0for several hours. The two solid fractions were combined and sublimed at13.8/high vacuum,

7 giving colorless rods M. P. 162-164, of the 13:14

dehydro ketone (XVIII).

The oil obtained by complete removal of solvent from the mother liquorswas dissolved in benzene (200 ccs.) and placed on a column of activatedmagnesium silicate (Florisil) (600 gms.) made up in the same solvent.The fractions obtained included the following;

Pure 13:14dehydro and 16:17 dehydro ketones (XVIII) I and (XIX) wereisolated from these latter fractions as described above in (A). p

EXAMPLE XXXI Conversion of the 13:14 dehydro ketone (XVIII) to dl-18-iz0r-D-h0m0andr0smn-3p-ol-1 7 a-one (XX) (A). IN NEUTRAL SOLUTION The13:14 dehydro ketone 1000 mgms., M. P. 163

165 was dissolved in ethanol (50 cos, distilled over Raney nickel),catalyst (30% Pd(OH)2/SrCOa, 300 mgms.) added, and the mixture shaken atan initial pres-- sure of 36.0 lbs/square inch of hydrogen. Thepressuredropped rapidly to 28.5 lbs., due to catalyst and solventuptake, and then to 18.0 lbs. during fifteen minutes.

' After filtration from the catalyst and removal of the for twelvehours, a colorless solid separated. The filtrate from this solidsolvent, a colorless oil was obtained which showed noabsorption in theultra-violet, and which crystallized partially on standing in thepresence of ether.

flux in ethanolic potassium hydroxide (50 cos. of 0.4 N); for one hour.After neutralization with glacial acetic acid, concentration underreduced pressure This residue from the reduction (oil plus solid) washeated under rei and isolation with benzene, the colorless resulting oilcrystallized from light petroleum inprisms, M. P. 157 160.Recrystallization from aqueous ethanol gave the desired compound (XX) M.P 158461", unchanged by sublimation at 142" /high vacuum;

' (B) IN THE PRESENCE 'OF BASE The 13.14 'dehydro ketone 901 mgms, M. P.161- 164) in ethanol (150 ccs.,.distilled over Raney nickel) andcontaining potassium hydroxide (60 mgms.) was shaken under an initialpressure of 38.0 lbs/square inch group during yield matted needles, M.P. 142-145 tion through the bisulfite addition compound and recrystal-20 of hydrogen in the presence of 10% Pd/ C (300 mgms.')-.I Reductionproceeded rapidly, absorption having ceased after ten minutes.Neutralization, removal of solvent, and isolation of the product in thenormal manner gave (XX) as a colorless oil which crystallized from lightpetroleum (B. P. -100), M. P. 157159.

EXAMPLE XXXII Conversion of 16:17 dehydro ketone (XIX) to til-18nor-D-homoandrostan-3fi-0l-17oz-0ne' (XX) The 16 :17 dehydro ketone (470mgms.) was dissolved in ethanol (20 00s., distilled over Raney nickel)and 10% Pd/C catalyst (commercial, mgms.) added.- The mixture, wasstirred with hydrogen at atmospheric pressure, the theoreticalabsorption being complete in nine minutes, after which absorptionceased. The cata-. lyst was removed by filtration, and the solventdistilled off at reduced pressure, yielding a colorless oil whichcrystallized in colorless prisms on adding light petroleum (B. P.90-100"). The saturated keto-alcohol (XX) was obtained with a M. P.158-160".

EXAMPLE XXXIH Conversion of the keto-alcohol compound (XX) to al-18-nor-D-homoandrostane-3,1 7u-a'ione (XXI) To a solution of 0.29 gm. ofthe saturated keto-alcohol (XX) in 20ml. of acetic acid was added 0.88gm. of chromic anhydride in 1.0 ml. of water. After eight hours thesolution was poured into aqueous sodium carbonate.

After standing overnightthe resulting precipitate was filtered, washedwith water and dried. The residue recovered had a M. P. 127142. Thismaterial was sub-' limed and then recrystallized from aqueous ethanol toFurther purificalization from methylcyclohexane raised the melting pointof the desired saturated diketo compound (XXI) to 149- 150.5". Thisproduct has androgenic activity. In chrys ene nomenclature compound (XX)in Example XXXI.

is trans-anti-trans-anti-trans-l-keto 8,8 hydroxy10amethyl-octadecahydrochrysene and compound (XXI) in Example XXXIII istrans-anti-trans-anti-trans-1,8-diketo- 10a-methyl-octahydrochrysene.

The various stereoisomers of the carbinol IX, e. g. VIII, XXV, XV, etc.can be analogously reduced to the corresponding stereoisomers ofstructure XX, and the lat-' ter oxidized to the stereoisomers of thediketone structure XXI. For example, the trans-anti-cis carbinol VIIIcan be reduced according to the procedure described above in ExamplesXXIX and XXXI or by catalytic hydrogenation of the aromatic ring. In thelatter case there was obtained a compound having the Formula XX withtransanti-cis-syn-trans configuration, and having the 'M. P. 129-1305.(Analysis-Called. for CisHanOz: C, 78.57; H, 10.41. Found C, 78.73; H,10.76.) Acetate, M. P. 168168.5. H, 9.70. Found: C, 76.09; H, 9.75.) Thelatter carbinol XX was oxidized with potassium chromate in glacialacetic acid to give 'a diketone of structure XXI withtransanti-cis-syn-trans configuration, and having the M. ,P.(Analysis.Calcd. for C19H28O2; C.

1235-1255". 79.12; H, 9.78. Found: c, 79.45; H, 10.06.)

In compounds I and 'IX and the other compounds hav ing'an RO groupatthel-position, the methoxy group can be replaced by other lower 'alkoxygroups such as ethoxy, propoxy, butoxy, etc. R, in addition to being alower alkyl group, can be any equivalent inert aliphatic groupcontaining from 1 to about 8 carbon atoms. The

-R or lower alkyl blocking group, for example, can contain a hydroxygroup or groups as well as a lower alkoxy group and include equivalentgroups such as 2-hydroxyethyl, 2,3-dihydroxypropyl, 2-methoxyethyl,Z-ethoXyethyl and the like. It serves merely as a blocking or protectivethe initial reactions and is removed'as shown (Analysis.-Calcd. forC21H32O3: C, 75.86;

21 in compounds XVIH and XIX to provide the desired keto group. Allreferences to melting and boiling points herein are given in C.

The compounds of the invention having a hydroxy group in the 8-positionof the chrysene nucleus can be utilized either in the free alcohol formor in the form of esters derived from carboxylic acids of relatively lowmolecular Weight, i. e. from one to about eight carbon atoms. The natureof the acyloxy groups in the 8-position of said esters is not critical,but preferred types are those derived from lower aliphatic carboxylicacids, monocycloaliphatic carboxylic acids and monocarbocyclic aromaticacids. Illustrative of such preferred types of acyl groups arelower-alkanoyloxy groups; e. g. formyloxy, acetoxy, propionoxy,butyroxy, isobutyroxy, valeryloxy, trimethylacetoxy, caproyloxy,isocaproyloxy, heptanoyloxy, octanoyloxy, and the like;carboxyl-lower-alkanoyloxy groups; e. g. hemi-succinyloxy,hemi-glutaryloxy, hemi-adipyloxy, and the like; and mono-carbocyclicaroyloxy groups, e. g. benzoyloxy, p-toluyloxy, p-nitrobenzoyloxy,3,5-dinitrobenzoyloxy, and the like. The acyloxy groups can containsubstituents such as nitro, methoxy, halogen, etc. which are inert tothe reaction conditions used for the preparation of the esters.

The present application is a continuation-in-part of our application,Serial No. 390,074, filed November 3, 1953, and now abandoned.

We claim:

1. A compound selected from the group consisting of 1 RO 8 Xa-methy1-5,6,6a,7,8,9,10,10a,11,12- decahydrochrysene and1-RO-8-X-10a-methyl-4b,5,6,6a,7;8,9,10,10a,10b,11,12-dodecahydrochrysene, in which R is a lower alkylblocking group and X is selected from the class consisting of hydroxy,acyloxy, keto and ethylenedioxy.

2. 1 methoxy 8 keto 10a methyl 4b,5,6,6a,7,8,9,10,10a,10b,11,12-dodecahydrochrysene.

3. 1 methoxy 8 keto 10a methyl 10,108.,11,12-decahydrochrysene.

4. 1 methoxy 8 hydroxy 10a methyl 4b,5,6,6a, 7,8,9,10,10a,10h,11,12-dodecahydrochrysene.

5. A compound selected from the group consisting of 1 keto 8 hydroxy 10amethyl 1,2,3,4,4b,5,6,6a, 7,8,9,10,10a,10b,11,12 hexadecahydrochryseneand 1- keto 8 hydroxy 10a methyl 1,4,4a,4b,5,6,6a,7,8,9,10,10a,10b,11,12,12a-hexadecahydrochrysene.

6. dl 18 nor D homo 13(14) androsten 3,6- ol-17a-one.

7. dl 18 nor D homo 16(17) androsten 3B- ol-17a-one.

8. A compound selected from the group consisting of 1 keto 8 hydroxy 10amethyl octadecahydrochrysene and 1,8 diketo 10a methyloctadecahydrochrysene.

9. The compound, dl-18-nor-D-homoandrostan-343-01- l7a-one.

10. The compound, dl 18 nor-D-hornoandrostane-3, 17a-dione.

11. The process of preparing the 13:14 dehydro and 16: 17 dehydroketones of claim 5, which comprises reducing 1 RO 8 hydroxy 10a methyl4b,5,6,6a,7,8, 9,10,10a,10b,11,12-dodecahydrochrysene, where R is alower alkyl group, in a liquid ammonia-alcoholic reaction mixture byaddition of lithium, and hydrolyzing the resulting intermediate byheating with aqueous acid.

12. The process which comprises reducing l-methoxy- 8 keto 10a methyl5,6,8,9,10,10a,11,12 octahydrochrysene in a liquidammonia-ethanol-lithium reaction mixture, hydrolyzing the resultingproduct by heating with aqueous acid and catalytically reducing withpalladium catalyst the resulting 13 (14)- and 16(17) dehydro ketones todl-18-nor-D-homoandrostan-3B-ol-17a-one.

13. The process which comprises reducing l-lower alkoxy 8 hydroxy 10amethyl 4b,5,6,6a,7,8,9,10,10a, 10b,11,12-dodecahydrochrysene in a liquidammonia-alcoholic-lithium reaction mixture, hydrolyzing the resultingproduct by heating in aqueous acid, catalytically reducing withpalladium catalyst the 13(14)- and 16(l7)-dehydro ketones to 1 keto8-hydroxy-10a-methyl-octadecahydrochrysene and oxidizing the latter withchromic oxide to 1,8-diketo-10a-methyl-octadecahydrochrysene.

OTHER REFERENCES Woodward et al.: I. Am. Chem. Soc. 74, 4223-4251(1952).

8. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF1-KETO-8-HYDROXY-10A-METHYL-OCTADECAHYDROCHRYSENE AND1,8-DIKETO-10A-METHYL-OCTADECAHYDROCHRYSENE.
 13. THE PROCESS WHICHCOMPRISES REDUCING 1-LOWERALKOXY-8-HYDROXY-10A-METHYL-4B,5,6,6A,7,8,9,10,10A,10B,11,12-DODECAHYDROCHRYSENE IN A LIQUID AMMONIA-ALCOHOLIC-LITHIUMREACTION MIXTURE, HYDROLYZING THE RESULTING PRODUCT BY HEATING INAQUEOUS ACID, CATALYTICALY REDUCING WITH PALLADIUM CATALYST THE13(14)-AND 16(17)-DEHYDRO-KETONES TO 1-KETO-8-HYDROXY-10A-METHYL-OCTADECAHYDROCHRYSENE AND OXIDIZING THE LATTER WITH CHROMIC OXIDE TO1,8-DIKETO-10A-METHYL-OCTADECAHYDROCHRYSENE.